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OSBPL10, RXRA and lipid metabolism confer African-ancestry protection against dengue haemorrhagic fever in admixed Cubans.
Sierra B, Triska P, Soares P, Garcia G, Perez AB, Aguirre E, Oliveira M, Cavadas B, Regnault B, Alvarez M, Ruiz D, Samuels DC, Sakuntabhai A, Pereira L, Guzman MG
(2017) PLoS Pathog 13: e1006220
MeSH Terms: African Continental Ancestry Group, Cuba, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Lipid Metabolism, Oligonucleotide Array Sequence Analysis, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Receptors, Steroid, Retinoid X Receptor alpha, Severe Dengue
Show Abstract · Added March 21, 2018
Ethnic groups can display differential genetic susceptibility to infectious diseases. The arthropod-born viral dengue disease is one such disease, with empirical and limited genetic evidence showing that African ancestry may be protective against the haemorrhagic phenotype. Global ancestry analysis based on high-throughput genotyping in admixed populations can be used to test this hypothesis, while admixture mapping can map candidate protective genes. A Cuban dengue fever cohort was genotyped using a 2.5 million SNP chip. Global ancestry was ascertained through ADMIXTURE and used in a fine-matched corrected association study, while local ancestry was inferred by the RFMix algorithm. The expression of candidate genes was evaluated by RT-PCR in a Cuban dengue patient cohort and gene set enrichment analysis was performed in a Thai dengue transcriptome. OSBPL10 and RXRA candidate genes were identified, with most significant SNPs placed in inferred weak enhancers, promoters and lncRNAs. OSBPL10 had significantly lower expression in Africans than Europeans, while for RXRA several SNPs may differentially regulate its transcription between Africans and Europeans. Their expression was confirmed to change through dengue disease progression in Cuban patients and to vary with disease severity in a Thai transcriptome dataset. These genes interact in the LXR/RXR activation pathway that integrates lipid metabolism and immune functions, being a key player in dengue virus entrance into cells, its replication therein and in cytokine production. Knockdown of OSBPL10 expression in THP-1 cells by two shRNAs followed by DENV2 infection tests led to a significant reduction in DENV replication, being a direct functional proof that the lower OSBPL10 expression profile in Africans protects this ancestry against dengue disease.
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13 MeSH Terms
Surfing a genetic association interaction network to identify modulators of antibody response to smallpox vaccine.
Davis NA, Crowe JE, Pajewski NM, McKinney BA
(2010) Genes Immun 11: 630-6
MeSH Terms: Algorithms, Antibody Formation, Cytochrome P-450 CYP1A1, Gene Regulatory Networks, Genes, Genome-Wide Association Study, Humans, Markov Chains, NADPH Oxidases, Phenotype, Polymorphism, Single Nucleotide, Retinoid X Receptor alpha, Smallpox Vaccine
Show Abstract · Added August 6, 2012
The variation in antibody response to vaccination likely involves small contributions of numerous genetic variants, such as single-nucleotide polymorphisms (SNPs), which interact in gene networks and pathways. To accumulate the bits of genetic information relevant to the phenotype that are distributed throughout the interaction network, we develop a network eigenvector centrality algorithm (SNPrank) that is sensitive to the weak main effects, gene-gene interactions and small higher-order interactions through hub effects. Analogous to Google PageRank, we interpret the algorithm as the simulation of a random SNP surfer (RSS) that accumulates bits of information in the network through a dynamic probabilistic Markov chain. The transition matrix for the RSS is based on a data-driven genetic association interaction network (GAIN), the nodes of which are SNPs weighted by the main-effect strength and edges weighted by the gene-gene interaction strength. We apply SNPrank to a GAIN analysis of a candidate-gene association study on human immune response to smallpox vaccine. SNPrank implicates a SNP in the retinoid X receptor α (RXRA) gene through a network interaction effect on antibody response. This vitamin A- and D-signaling mediator has been previously implicated in human immune responses, although it would be neglected in a standard analysis because its significance is unremarkable outside the context of its network centrality. This work suggests SNPrank to be a powerful method for identifying network effects in genetic association data and reveals a potential vitamin regulation network association with antibody response.
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13 MeSH Terms
Association between polymorphic variation in VDR and RXRA and circulating levels of vitamin D metabolites.
Hibler EA, Jurutka PW, Egan JB, Hu C, LeRoy EC, Martinez ME, Thompson PA, Jacobs ET
(2010) J Steroid Biochem Mol Biol 121: 438-41
MeSH Terms: Biomarkers, Calcifediol, Calcitriol, Genetic Variation, Genotype, Humans, Models, Biological, Models, Genetic, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Principal Component Analysis, Receptors, Calcitriol, Retinoid X Receptor alpha, Transcription, Genetic, Vitamin D
Show Abstract · Added December 29, 2014
The vitamin D metabolite 1,25(OH)2D is the bioactive ligand of the vitamin D receptor (VDR). VDR forms a heterodimer with the retinoid X receptors (RXRs) that when bound to ligand influences the transcriptional control of genes that regulate circulating levels of vitamin D metabolites. Whether genetic variation in VDR or RXRA affects circulating levels of 1,25(OH)2D or 25(OH)D has not been established. We used a single nucleotide polymorphism (SNP) tagging approach to evaluate the association between SNPs in VDR and RXRA and serum levels of 1,25(OH)2D and 25(OH)D. A total of 42 tagSNPs in VDR and 32 in RXRA were analyzed in a sample of 415 participants. Principal components analyses revealed a gene-level association between RXRA and serum 1,25(OH)2D concentrations (P=0.01), but not 25(OH)D. No gene-level association was found for VDR with either serum biomarker. At the single-SNP level, a significant positive trend was observed for increasing 1,25(OH)2D levels with each additional copy of the A allele for RXRA SNP rs9409929 (P-trend=0.003). After a multiple comparisons adjustment, no individual SNP in VDR or RXRA was significantly associated with either outcome. These results demonstrate an association between genetic variation in RXRA and 1,25(OH)2D serum concentrations.
Copyright (c) 2010 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Genetic polymorphisms in vitamin D receptor VDR/RXRA influence the likelihood of colon adenoma recurrence.
Egan JB, Thompson PA, Ashbeck EL, Conti DV, Duggan D, Hibler E, Jurutka PW, Leroy EC, Martínez ME, Mount D, Jacobs ET
(2010) Cancer Res 70: 1496-504
MeSH Terms: Adenoma, Adult, Aged, Aged, 80 and over, Clinical Trials, Phase III as Topic, Colonic Neoplasms, Double-Blind Method, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Receptors, Calcitriol, Recurrence, Retinoid X Receptor alpha
Show Abstract · Added December 29, 2014
Low circulating levels of vitamin D affect colorectal cancer risk. The biological actions of the hormonal form of vitamin D, 1,25(OH)(2)D(3), are mediated by the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptors (RXR). Using a single nucleotide polymorphism (SNP) tagging approach, we assessed the association between genetic variations in RXRA and VDR and odds of recurrent (metachronous) colorectal neoplasia in a pooled population of two studies. A total of 32 tag SNPs in RXRA and 42 in VDR were analyzed in 1,439 participants. A gene-level association was observed for RXRA and any (P = 0.04) or proximal (P = 0.03) metachronous neoplasia. No gene-level associations were observed for VDR, nor was any single SNP in VDR related to any metachronous adenoma after correction for multiple comparisons. In contrast, the association between RXRA SNP rs7861779 and proximal metachronous neoplasia was of borderline statistical significance [odds ratio (OR), 0.68; 95% confidence interval (95% CI), 0.53-0.86; unadjusted P = 0.001; adjusted P = 0.06], including when observed independently in each individual study. Haplotypes within linkage blocks of RXRA support an approximately 30% reduction in odds of metachronous neoplasia arising in the proximal colon among carriers of specific haplotypes, which was strongest (OR(proximal), 0.67; 95% CI, 0.52-0.86) for carriers of a CGGGCA haplotype (rs1805352, rs3132297, rs3132296, rs3118529, rs3118536, and rs7861779). Our results indicate that allelic variation in RXRA affects metachronous colorectal neoplasia, perhaps of particular importance in the development of proximal lesions.
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17 MeSH Terms
Malignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes.
Indra AK, Castaneda E, Antal MC, Jiang M, Messaddeq N, Meng X, Loehr CV, Gariglio P, Kato S, Wahli W, Desvergne B, Metzger D, Chambon P
(2007) J Invest Dermatol 127: 1250-60
MeSH Terms: 9,10-Dimethyl-1,2-benzanthracene, Animals, Carcinogens, Cell Transformation, Neoplastic, Epidermis, Gene Expression Regulation, Neoplastic, Keratinocytes, Mice, Mice, Transgenic, Nevus, Pigmented, PPAR gamma, Papilloma, Retinoid X Receptor alpha, Skin Neoplasms, Tetradecanoylphorbol Acetate
Show Abstract · Added February 25, 2015
Retinoid-X-receptor alpha (RXRalpha), a member of the nuclear receptor (NR) superfamily, is a ligand-dependent transcriptional regulatory factor. It plays a crucial role in NR signalling through heterodimerization with some 15 NRs. We investigated the role of RXRalpha and its partners on mouse skin tumor formation and malignant progression upon topical DMBA/TPA treatment. In mutants selectively ablated for RXRalpha in keratinocytes, epidermal tumors increased in size and number, and frequently progressed to carcinomas. As keratinocyte-selective peroxisome proliferator-activated receptor gamma (PPARgamma) ablation had similar effects, RXRalpha/PPARgamma heterodimers most probably mediate epidermal tumor suppression. Keratinocyte-selective RXRalpha-null and vitamin-D-receptor null mice also exhibited more numerous dermal melanocytic growths (nevi) than control mice, but only nevi from RXRalpha mutant mice progressed to invasive human-melanoma-like tumors. Distinct RXRalpha-mediated molecular events appear therefore to be involved, in keratinocytes, in cell-autonomous suppression of epidermal tumorigenesis and malignant progression, and in non-cell-autonomous suppression of nevi formation and progression. Our study emphasizes the crucial role of keratinocytes in chemically induced epidermal and melanocytic tumorigenesis, and raises the possibility that they could play a similar role in UV-induced tumorigenesis, notably in nevi formation and progression to melanoma.
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15 MeSH Terms
Functional role of RXRs and PPARgamma in mature adipocytes.
Metzger D, Imai T, Jiang M, Takukawa R, Desvergne B, Wahli W, Chambon P
(2005) Prostaglandins Leukot Essent Fatty Acids 73: 51-8
MeSH Terms: Adipocytes, Animals, Cell Death, Cell Differentiation, Dimerization, Genetic Predisposition to Disease, Mice, Mice, Transgenic, Obesity, PPAR gamma, Retinoid X Receptor alpha, Retinoid X Receptor gamma, Sodium Glutamate, Tamoxifen
Show Abstract · Added February 25, 2015
The peroxisome proliferator-activated receptor gamma (PPARgamma) is abundantly expressed in adipocytes, and plays an important role in adipocyte differentiation and fat accretion. It is a heterodimeric partner of the retinoid X receptors alpha, beta and gamma, which are also expressed in the adipose tissue. As lethality of PPARgamma(-/-) and RXRalpha(-/-) mouse fetuses precluded the analysis of PPARgamma and RXRalpha functions in mature adipocytes, we generated RXRalpha(ad-/-) and PPARgamma(ad-/-) mice, in which RXRalpha and PPARgamma are selectively ablated in adult adipocytes, respectively. Even though the adiposity of RXRalpha(ad-/-) mice is similar to that of control mice when fed a regular diet, they are resistant to chemically and dietary-induced obesity. However, mature adipocytes lacking either both RXRalpha and RXRgamma or PPARgamma die, and are replaced by newly formed adipocytes. Thus, in adipocytes, RXRalpha is essential for lipogenesis, but RXRgamma can functionally replace RXRalpha for the adipocyte vital functions exerted by PPARgamma/RXR heterodimers.
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14 MeSH Terms